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CME / ABIM MOC / CE

Can Certain Antihypertensive Drug Classes Help Prevent Diabetes?

  • Authors: News Author: Nancy A. Melville; CME Author: Laurie Barclay, MD
  • CME / ABIM MOC / CE Released: 1/7/2022
  • Valid for credit through: 1/7/2023
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

    Nurses - 0.25 ANCC Contact Hour(s) (0.25 contact hours are in the area of pharmacology)

    Pharmacists - 0.25 Knowledge-based ACPE (0.025 CEUs)

    IPCE - 0.25 Interprofessional Continuing Education (IPCE) credit

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for diabetologists/endocrinologists, family medicine/primary care clinicians, internists, cardiologists, nephrologists, public health and prevention officials, nurses, pharmacists, and other members of the health care team for patients with or at risk for type 2 diabetes.

The goal of this activity is to describe the effect of blood pressure lowering per se on the risk for new-onset type 2 diabetes, based on a meta-analysis by the Blood Pressure Lowering Treatment Trialists' Collaboration of randomized controlled trials investigating the differential effects of five major classes of antihypertensive drugs, including renin-angiotensin system blockers (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers and calcium-channel blockers).

Upon completion of this activity, participants will:

  • Assess the effect of blood pressure lowering per se on the risk for new-onset type 2 diabetes, based on a meta-analysis including 1-stage individual participant data meta-analysis of randomized controlled trials
  • Evaluate the clinical implications of the effect of blood pressure lowering per se on the risk for new-onset type 2 diabetes, based on a 1-stage individual participant data meta-analysis of randomized controlled trials
  • Outline implications for the healthcare team


News Author

  • Nancy A. Melville

    Freelance writer, Medscape

    Disclosures

    Disclosure: Nancy A. Melville has disclosed no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Editor/Nurse Planner

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.

CME Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Amanda Jett, PharmD, BCACP, has disclosed no relevant financial relationships.

None of the nonfaculty planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Mitigation

All of the relevant financial relationships listed for these individuals have been mitigated.


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CME / ABIM MOC / CE

Can Certain Antihypertensive Drug Classes Help Prevent Diabetes?

Authors: News Author: Nancy A. Melville; CME Author: Laurie Barclay, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 1/7/2022

Valid for credit through: 1/7/2023

processing....

Clinical Context

Type 2 diabetes prevalence among adults is currently approximately 9% worldwide and is increasing in many regions. Individual studies have shown that renin-angiotensin system (RAS) inhibitors may reduce risk for new-onset type 2 diabetes, whereas diuretics may increase risk.

Study Synopsis and Perspective

Lowering blood pressure, which is known to prevent the vascular complications of type 2 diabetes, can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)--so-called RAS blockers--showed the strongest association with preventive effects; conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk for new-onset diabetes.

"This study suggests that blood pressure lowering can help prevent diabetes in addition to its well established beneficial effects in reducing cardiovascular events," write Milad Nazarzadeh and colleagues from the Blood Pressure Lowering Treatment Trialists' Collaboration in their article published in the Lancet.[1]

"The differing effects of some drug classes also support decision making for [antihypertensive] drug choice according to an individual's risk profile," note Nazarzadeh, from Deep Medicine, Oxford Martin School, University of Oxford, United Kingdom, and colleagues.

"In particular, [RAS inhibitors, ACE inhibitors, and ARBs] should become the drugs of choice when clinical risk of diabetes is of concern, whereas β blockers and thiazide diuretics should be avoided where possible," they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, from the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.[2]

"Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes," they write.

They note that although "the absolute risk reduction found in this meta-analysis is modest...interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension."

Commenting on the findings to the UK Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, United Kingdom, said: "Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in the Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear."

Kevin McConway, PhD, emeritus professor of applied statistics, the Open University, United Kingdom, similarly concurs: "Though there is good evidence that lowering people's blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn't been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study."

RAS Blockers Associated With Lower Diabetes Risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

During a median follow-up of 4.5 years, 9883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk for new-onset diabetes that was nearly identical (risk reduction [RR], 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk for type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk for diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5 mm Hg was associated with an 11% reduced risk of developing diabetes.

"The relative magnitude of reduction per 5 mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events," the authors say.

"[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies," they add.

In the opposite direction, research has suggested that each 20 mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk for type 2 diabetes, but the causality of that association is uncertain, the authors note.

Results Fill Gap in Evidence for Guidelines

The meta-analysis findings were further validated in a supplemental Mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk for diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St George's, University of London, told the UK Science and Media Centre: "This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes." 

Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself or by some other effect of the antihypertensive drugs has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that "our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardised fixed degree of blood pressure reduction."

"With consistent results from both randomised controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease," they state.

Authors of US Hypertension Guidelines Should Follow Lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension, however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

With an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, however, the need for more measures to tackle the problem is urgent, say Dr Cavender and Dr Wirka in their editorial.

"Perhaps these data are enough to encourage the writers of the hypertension guidelines in the US to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria," they state.

Lancet. 2021;398:1778-1779, 1803-1810.

Study Highlights

  • This meta-analysis pooled data (n=145,939; 60.6% men) from 22 studies conducted between 1973 and 2008, including all primary and secondary prevention trials using a specific class or classes of antihypertensive drugs versus placebo or other classes of antihypertensives with at least 1000 person-year follow-up in each randomly allocated group.
  • Participants with baseline diagnosis of diabetes and trials among patients with prevalent diabetes were excluded.
  • After a median follow-up of 4.5 years (interquartile range, 2.0 years), 9883 participants developed new-onset type 2 diabetes.
  • A 5 mm Hg systolic blood pressure reduction lowered type 2 diabetes risk by 11% (hazard ratio, 0.89; 95% confidence interval [CI], 0.84-0.95).
  • Compared with placebo, ACE inhibitors (relative risk [RR], 0.84; 95% CI, 0.76-0.93) and ARBs (RR, 0.84; 95% CI, 0.76-0.92) lowered risk for new-onset type 2 diabetes, β-blockers (RR, 1.48; 95% CI, 1.27-1.72]) and thiazide diuretics (RR, 1.20; 95% CI, 1.07-1.35) increased risk, and calcium-channel blockers (RR, 1.02; 95% CI, 0.92-1.13) had no effect.
  • The investigators concluded that blood pressure lowering effectively prevents new-onset type 2 diabetes, with 11% risk reduction per 5 mm Hg lower systolic blood pressure.
  • This relative effect size is similar to those seen for prevention of major cardiovascular disease.
  • However, antihypertensives have qualitatively and quantitatively different effects on diabetes, likely because of differing off-target effects, with outcomes most favorable for ACE inhibitors and ARBs and with thiazide diuretics and beta blockers actually increasing risk.
  • It is therefore prudent to consider the overall effect of specific drug classes regardless of the degree of blood pressure reduction in trials.
  • The adverse effect of beta blockers and thiazide diuretics on type 2 diabetes risk supports recommendations to classify these as low priority for treating hypertension when risk for diabetes or prediabetes is of clinical concern.
  • Renin-angiotensin-aldosterone system deactivation may causally lower type 2 diabetes risk, in part by reducing inflammatory marker concentration, independent of the blood pressure-lowering effect.
  • Randomized controlled trial findings were largely confirmed in independent complementary analysis using genetic data.
  • The findings show that elevated blood pressure is a modifiable risk factor for new-onset type 2 diabetes in people without a type 2 diabetes diagnosis and support the indication for selected classes of antihypertensive drugs for diabetes prevention, which could further refine the selection of drug choice based on an individual's clinical risk for type 2 diabetes.
  • Clinicians and health policy makers therefore have an opportunity to modify disease risk, either through use of appropriate antihypertensive medications or by promoting lifestyle behaviors known to reduce blood pressure, including maintaining a healthy weight through physical activity and balanced diet.
  • This is especially important given the generally disappointing pharmacological interventions through glucose-modifying pathways and observed increased type 2 diabetes risk with lipid-lowering treatments.
  • Specific biological pathways by which elevated blood pressure causes new-onset type 2 diabetes are unknown, but may include insulin resistance, vascular inflammation, endothelial dysfunction, increased sympathetic nervous system activation, and chronic inflammation.

Clinical Implications

  • Blood pressure lowering effectively prevents new-onset type 2 diabetes, with 11% risk reduction per 5 mm Hg lower systolic blood pressure.
  • The findings support the indication for selected classes of antihypertensive drugs for diabetes prevention.
  • Implications for the Health Care Team: Members of the healthcare team should be aware that RAS blockers are most likely to reduce type 2 diabetes risk, whereas thiazides and beta-blockers should be avoided.

 

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